Controlled-release salt sensitive capsule for oral use and adhesive system

ABSTRACT

A salt sensitive capsule has been developed which dissolves in the mouth and releases the encapsulated internal ingredient(s). The outer salt sensitive shell maintains its integrity when kept at a preselected aqueous salt concentrations. When introduced into the mouth, the degree of salinity is lower and causes the sheel to disassociated and release the internal component. The capsules may be associated with an adhesive system so that the capsules are topically applied to mouth tissue. The adhesive system is compatible with maintanance of the salt sensitive shell.

This application is a continuation-in-part of U.S. Ser. No. 7/183,591with a filing date of Apr. 19, 1988 abandoned and entitled"Controlled-Release Capsules By The Use Of A Salt Sensitive ShellMaterial", Chel W. Lew, inventor.

BACKGROUND OF THE INVENTION

Encapsulation processes have been developed to make very small capsulescontaining a selected compound or mixture coated with a layer of anothercomposition. The capsules can be in the size range of about 1 micron toseveral millimeters. The smallest capsules can be used in emulsionformulas. The smaller capsules are sometimes referred to asmicrocapsules.

Some microcapsules are designed to break under pressure so that theinternal compound is released when rubbed over a surface. Microcapsuleshave been used containing therapeutic agents to be ingested coated withfilms broken down due to pH increases in the gastric system. Other filmsor shells on capsules are soluble in particular solvents. Release of theinternal component is governed generally by solubility characteristicsand the thickness of the shell.

The microcapsules are made by methods well known in art and have beenused in various industrial and commercial applications. Typicalprocesses are centrifugal extrusion, pan coating and air suspensionmethods. U.S. Pat. Nos. 3,692,690; 3,015,128 and 3,310,612 are exemplaryof encapsulation techniques known and practiced in the art. In additionto those illustrated by the patents, other techniques are available. Thepresent invention can utilize any of the available methods for preparingcapsules or microcapsules.

SUMMARY OF THE INVENTION

The invention is a capsule for oral use containing an internal activeingredient which is coated with a shell of a non-toxic salt sensitivematerial. The salt sensitive capsules may be associated with an adhesionsystem. In this invention salt sensitivity relates to the integrity ofthe shell of the capsule or microcapsule in varying concentrations ofsalt in solution. The salt sensitive compositions are a rigid gel andinsoluble when the salt level in an aqueous solution is maintained at apreselected level. Decreasing the level of salt by diluting the solutioncontaining the capsules causes the salt sensitive shell to lose itsstructure, break down and dissolve. There are a number of polymers whichare insoluble at certain preselected salt levels, depending on thepolymer and salt used, and soluble at a lower salt levels.

The adhesive system associated with the salt sensitive encapsulatedactive ingredient does not affect the integrity of the capsule shell.The adhesive may be associated with the outer shell. The adhesive systemmay also be an adhesive in an aqueous gel with a salt concentration ofthe gel adjusted to the preselected level to maintain the integrity ofthe capsule shell.

The capsules are designed so that when they are placed in the humanmouth with the normal salt (electrolytes) concentration, the capsulesdissolve. The shell's composition can be formulated to provide slow orfast rate of dissolution. The capsules used with the adhesive systemprovide a mixture which can be placed inside the mouth on selectedtissue. The capsules dissolve over a sustained period of time while theadhesion system holds them in place. The active ingredient is releasedover time in a specific region of the oral cavity.

The characteristics of the active ingredient to be enclosed must beconsidered in designing the capsule of this invention. A water solubleactive ingredient is not to be encapsulated with a water soluble saltsensitive shell. If the active ingredient is water soluble, a waterinsoluble film layer must enclose the active ingredient which in turn iscoated with the salt sensitive shell. There would be a two layer processfor encapsulation so that the internal soluble ingredient will beprotected from the salt sensitive shell with the water insoluble layer.The water insoluble layer is water dispersible so that the activeingredient is released once the capsule is placed in sufficientlydiluted concentrations of salt to dissolve the salt sensitive layerexposing the water insoluble layer.

DETAILED DESCRIPTION OF THE INVENTION

The following description of the invention is for particular embodimentsof capsules including microcapsules that can be used for oralmedication. The invention is for a non-toxic, salt sensitive shell forrelease of an active ingredient such as medication or a breath freshenerin the mouth. The active ingredient is contained inside the shell and isnot released until the shell dissolves in the mouth. The alternativeembodiment is the mixture of the capsules in a non-toxic adhesive systemin which the bioadhesive is part of the outer shell of the capsules orthe bioadhesive is a gel containing the capsules. The adhesive system iscompatible with the salt sensitive shell such that the integrity of theshell is not affected by the adhesive.

A salt sensitive shell can be used in a single layer capsule toencapsulate a water insoluble ingredient. A water soluble activeingredient cannot be effectively encapsulated with a salt sensitivelayer which reacts to water soluble compounds. Also, certain otheractive ingredients may be reactive with the compound or compoundsselected for the salt sensitive shell. In instances where the internalcomponent of the capsule cannot be in contact with the salt sensitivecompound a non-toxic water insoluble and/or nonreactive layer of filmencapsulates the internal component which in turn is coated with anouter shell of salt sensitive compound. The capsule has a two layercoating. The water insoluble compound should be water dispersible sothat the active internal ingredient will be released in solution. Theinternal component of the capsule will be released upon the dissolutionof the salt sensitive outer layer in a diluted salt concentration leveland the following dispersal of the insoluble layer.

The capsules can be made as microcapsules using known encapsulationtechniques such as centrifugal extrusion, pan coating and airsuspension. The capsules of this invention include microcapsules and thebroad categories of known capsules and encapsulation techniques Thefollowing Table 1 are examples of non-toxic salt sensitive materials.The materials are salted out of solution at a certain level of saltconcentration and are insoluble. Table 1 has the maximum saltconcentration for solubility. The mouth environment does not contain ahigh enough salt concentration to maintain the integrity of the capsuleswhich would dissolve in the oral cavity.

                  TABLE 1*                                                        ______________________________________                                                    Max. Salt Conc. for Solubility                                                wt. % in sol'n of salt                                            Salt Sensitive Material                                                                     NaCl    Na.sub.2 SO.sub.4                                                                      Na.sub.2 CO.sub.3                                                                    Na.sub.2 PO.sub.4                       ______________________________________                                        Polyvinyl alcohol                                                                           14%     4%       4%     9%                                      (PVA)                                                                         Methyl Cellulose (MC)                                                                       11      6        4      2.9                                     Hydroxypropyl Methyl-                                                                       17      6        5      3.9                                     (HPMC) Cellulose                                                              Ethylhydroxyethyl-                                                                           8      2.5      3      3                                       (EHEC) Cellulose                                                              ______________________________________                                         *Information from Handbook of Water Soluble Gums and Resins by Robert L.      Davidson (1980).                                                         

Other salt sensitive materials include polyethylene oxide andCarrageenan.

An example of non-toxic film for use with a water soluble internalcomponent is oil base Span®. The Span® materials are partial esters offatty acids and hexitiol anhydrides and the food grade acceptable Spans®would be suitable. Also edible fats such as triglycerides would besuitable.

An example of a water insoluble compound used in this invention as theinternal active ingredient is ethyl aminobenzoate. This compound, alsoknown as benzocaine, is used as a local or topical anesthetic in themouth. Benzocaine is relatively insoluble in water as one gram dissolvesin about 2500 ml. Benzocaine is used at about 5% to 20% strength in asuitable carrier for anesthetics. For the purpose of this specificationand claims, the water insoluble active ingredients can have some slightsolubility in water such as benzocaine. Capsules of benzocaine areprepared using a salt sensitive shell. The shell is formulated todissolve in the electrolyte concentration of the mouth releasing thebenzocaine.

Other active ingredients to be encapsulated can be antibiotics capableof oral delivery such as bankcomycin, gentamicin, imipenem andceptazidime. The antibiotics of this invention may be water soluble orwater insoluble and are defined us oral antibiotics for the terminologyof this invention.

The capsules may be included in an aqueous gel adhesive system which hasa salt concentration of a preselected level high enough to maintain theintegrity of the outer shell of the capsule surrounding the activeingredient. More than one active ingredient may be included inside theshell as long as the active ingredient does not adversely affect theshell by chemically reactivity or otherwise. For instance, a waterinsoluble flavoring oil may be mixed with the benzocaine for an oralanesthetic. The encapsulated component may be a mixture of ingredients.The active component can be any ingredient desired to be released in themouth.

Examples of bioadhesives which can be used as a capsule coating or in agel adhesive system are calcium polycarbophil, polyacrylic acid,gelatin, CMC, natural gums such as karaya and tragacanth, algin,chitosan, HPMC, starches, pectins and mixtures thereof. Compounds suchas CMC or HPMC may have adhesive qualities as well as salt sensitivity.The adhesives are coated on the capsule shell or made part of thecapsule shell provided there is compatibility with the shell compositionto maintain integrity.

The adhesives may be mixed with a hydrocarbon gel base, composed ofpolyethylene and mineral oil, with a preselected salt level to maintainthe capsule integrity.

The adhesive gel is adjusted to a preselected salt concentration with anon-toxic salt. The capsules are dispersed in the gel. The gelcontaining the capsules is applied to the tissue in the oral cavitywhere the delivery of the active ingredient is desired.

A typical bioadhesive aqueous gel system with benzocaine is comprised ofCMC 1-30%, Pectin 1-5%, gelatin 0.1-10.0% and polyethylene (5% inmineral oil) 10-35%, and the remainder is water.

The adhesives of this invention allow the capsules to be placed in themouth and adhere to the tissue in the oral cavity for a sustained periodof time for delivery of the antibiotic, local anesthetic, breathfreshener or other active ingredient.

What we claim is:
 1. A capsule for oral use comprising:at least oneinternal active ingredient which is water soluble; a non-toxic waterinsoluble, water dispersible film layer surrounding said internal activeingredient; a non-toxic shell encapsulating said film surrounding theactive ingredient and said shell is insoluble at a preselected saltconcentration; said shell dissolving at a salt concentration present inthe human mouth; said film dispersible in the human mouth; and anon-toxic adhesive system associated with the outer surface of saidshell which permits adhesion of the capsule to selected tissue insidethe mouth for a sustained period of time to allow for the dissolution ofsaid shell and said film and release of the active component.
 2. Acapsule for oral medication of claim 1 wherein said water solubleingredient is selected from the group consisting of water solubleantibiotics.
 3. A capsule for oral use of claim 1 wherein said non-toxicwater insoluble, water dispersible film layer is selected from the groupconsisting of food grade Span® and edible fats.
 4. A capsule for oraluse of claim 1 wherein said non-toxic salt sensitive shell is selectedfrom the group consisting of polyvinyl alcohol, methyl cellulose,hydroxypropyl cellulose, hydroxypropyl methyl cellulose,ethylhydroxyethyl cellulose, polyethylene oxide and Carrageenan.
 5. Acapsule for oral use of claim 1 wherein the non-toxic adhesion system isselected from the group consisting of calcium polycarbophil, polyacrylicacid, gelatin, CMC, natural gums, algin, chitosan, HPMC, starches,pectins and mixtures thereof which are applied to the outside of theshell of the capsules.
 6. An oral usage formulation comprising:capsulesmade of at least one internal active water insoluble ingredient with anon-toxic shell encapsulating said internal active component which isinsoluble at a preselected salt concentration with said composition ofsaid shell dissolving at the salt concentration present in the humanmouth and; said capsules contained in a non-toxic adhesive system suchthat the mixture of the capsules and the adhesive allows for theadhesion of the mixture to selected tissue inside the mouth for asustained period of time to allow for the dissolution of the shell andthe dispersal of the film layer and the release of the activeingredient.
 7. An oral usage formulation of claim 6 wherein saidnon-toxic adhesive system comprising an aqueous gel with a saltconcentration at a preselected level to maintain the integrity of thesalt sensitive shell of the capsule.
 8. The method of delivering anactive ingredient to the oral cavity comprising the stepsof:encapsulating an active ingredient with an inner shell layercomprised of a water insoluble, water dispersible, nonreactive filmlayer to form a microcapsule; further encapsulating the activeingredient with another layer comprised of a salt sensitive materialwhich is insoluble at a preselected salt level in an aqueous solution toform a microcapsule with two layers around the active ingredient;associating a plurality of microcapsule with an adhesive system whichdoes not affect the integrity of the shell; maintaining the integrity ofthe microcapsule by keeping the microcapsules in an aqueous solutionhaving a salt concentration at which said salt sensitive material isinsoluble soluble; and introducing the microcapsule having the adhesivesystem associated therewith into the oral cavity, the adhesive systemcausing the microcapsule to adhere to a selected site in the oral cavityfor a sustained period of time, the salt concentration present in theoral cavity being lower than the threshold salt concentration at whichthe salt sensitive material is soluble such that the salt sensitivematerial comprising the outer layer of the microcapsule dissolves andthe water dispersible layer dissolves, releasing the active ingredientat the selected site in the oral cavity.
 9. The method of claim 28additionally comprising encapsulating an active ingredient with an innershell of a water insoluble, water dispersible film layer beforeencapsulating with salt sensitive material.
 10. A delivery system forthe oral cavity comprisinga plurality of microcapsules with at least oneactive ingredient surrounded by an inner layer of a film of a waterinsoluble, water dispersible film and an outer shell that is insolubleat a preselected salt level in an aqueous solution and dissolves in theoral cavity; an adhesive associated with the outer shell of themicrocapsule which does not affect the integrity of the outer shell; andsaid adhesive causing adhesion of the microcapsules to the oral cavityfor a sustained period of time to allow dissolution of the shell andrelease of the active ingredient.
 11. A delivery system for the oralcavity of claim 10 comprising an inner layer of a film of a waterinsoluble, water dispersible, non-reactive film.
 12. A microcapsule ofclaim 1 wherein said film layer is non-reactive with said activeingredient.
 13. A microcapsule of claim 12 wherein said film layer isselected from the group consisting of oil based compounds and ediblefats.